EP1327450A1 - Oral vaccination - Google Patents

Oral vaccination Download PDF

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Publication number
EP1327450A1
EP1327450A1 EP02000901A EP02000901A EP1327450A1 EP 1327450 A1 EP1327450 A1 EP 1327450A1 EP 02000901 A EP02000901 A EP 02000901A EP 02000901 A EP02000901 A EP 02000901A EP 1327450 A1 EP1327450 A1 EP 1327450A1
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EP
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Prior art keywords
antigen
substance
medicament according
gastric acid
mimotopes
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EP02000901A
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German (de)
French (fr)
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EP1327450B1 (en
Inventor
Erika Jensen-Jarolim
Otto Scheiner
Hubert Pehamberger
Christoph Zielinski
Heimo Breiteneder
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Bio Life Science Forschungs- und Entwicklungsgesmbh
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Bio Life Science Forschungs- und Entwicklungsgesmbh
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Priority to AT02000901T priority Critical patent/ATE369875T1/en
Application filed by Bio Life Science Forschungs- und Entwicklungsgesmbh filed Critical Bio Life Science Forschungs- und Entwicklungsgesmbh
Priority to ES02000901T priority patent/ES2294051T3/en
Priority to DE50210696T priority patent/DE50210696D1/en
Priority to EP02000901A priority patent/EP1327450B1/en
Priority to ES03708059T priority patent/ES2286409T3/en
Priority to AT03708059T priority patent/ATE361097T1/en
Priority to DE50307169T priority patent/DE50307169D1/en
Priority to US10/501,402 priority patent/US20050226894A1/en
Priority to IL16285703A priority patent/IL162857A0/en
Priority to EP03708059A priority patent/EP1465658B1/en
Priority to CA002473416A priority patent/CA2473416A1/en
Priority to AU2003212215A priority patent/AU2003212215B9/en
Priority to PCT/EP2003/000369 priority patent/WO2003059380A2/en
Publication of EP1327450A1 publication Critical patent/EP1327450A1/en
Priority to IL162857A priority patent/IL162857A/en
Application granted granted Critical
Publication of EP1327450B1 publication Critical patent/EP1327450B1/en
Priority to US12/656,491 priority patent/US20100183684A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/35—Allergens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A61K2039/542—Mucosal route oral/gastrointestinal

Definitions

  • the present invention relates to a pharmaceutical for oral Vaccination.
  • the invention is based on the finding that parenteral Application can be avoided if in the stomach area suitable conditions prevail that affect the effectiveness of the vaccine do not interfere.
  • the present invention relates to medicinal products which are used as Antigenic substance and a gastric acid reducing substance as Combination preparation for joint or separate, simultaneous or contain staggered oral application for vaccination.
  • these medicinal products make it possible for them to act as antigens active substance simultaneously with the gastric acid-reducing Substance can be taken, both phases together or available separately.
  • the combination preparation can also be used in be applied in such a way that the substance which acts as an antigen separately and after application of a suitable dose gastric acid reducing substance is administered. It is important that the stomach acid at the time of application, that is to say When the vaccine got into the stomach compared to "normal gastric acidity" is reduced. That way it will enables a traditional parenteral vaccine can also be administered orally and its effect in the form of generation can develop an immune response. Furthermore, the reduced Acidity also results in non-activation of the gastric proteases, because Pepsinogens only become active through the low pH in the stomach Split pepsins.
  • the drugs are preferably used to vaccinate Mammals. Because animals can both develop tumors as well are able to produce IgE is also used in veterinary medicine Vaccination range according to the present invention think. Furthermore, it is also suspected that IgE in the defense against Parasitic infections in animals play a role, which also affects in this area an area of application of the present vaccination according to the invention results.
  • one as an antigen active substance and a gastric acid reducing substance can act as an antigen in the stomach at the same time or with time delay compared to the gastric acid reducing Substance are released. It is only important that the gastric environment is set in such a way that the substance acting as antigen is its Can have an effect on the generation of an immune response. Some individuals can be pathophysiologically or iatrogenically induced have reduced stomach acid for various reasons. For the However, vaccination according to the invention is necessary, targeted and controls to influence the acidity.
  • the gastric acid-reducing substance preferably consists of a Inhibiting gastric acid formation and / or binding the gastric acid Substance. This ensures that the way it is used Gastric acid reduction comes from different mechanisms of action can be based.
  • the stomach acid concentration can be increased by such means the needs of the vaccination according to the invention are adjusted.
  • Preferred gastric acid reducing agents are those which belong to the families of active substances of the antacids, H 2 receptor antagonists or proton pump inhibitors.
  • antacids ie basic agents
  • H 2 receptor antagonists inhibit histamine H 2 receptors competitively and reversibly, thereby reducing gastric acid formation.
  • Proton pump inhibitors in turn reduce gastric acidity by directly influencing acid secretion.
  • antacids sodium hydrogen carbonate, calcium carbonate, magnesium carbonate, magnesium hydroxide and magnesium hydroxide gel, magnesium silicate, aluminum phosphate, aluminum hydroxide and aluminum hydroxide gel, hydrotalcites, magaldrate, dihydroaluminum sodium carbonate, magnesium aluminate hydrate, aminoacetic acid and bismuth salts , Carbenoxolone and sucralate (aluminum hydroxide and sucrose sulfate) may be mentioned as substances which have a protective action via the mucous membrane.
  • H 2 -receptor blockers are: cimetidine, ranitidine, oxmetidine, famotidine, roxatidine and nizatidine.
  • proton pump inhibitors examples include: omezaprol, lansoprazole, pantoprazole and rabeprazole. Since anticholinergics include an inhibition of saliva u. Gastric juice secretion can also be used, representatives of this class, such as Pirenzepin.
  • gastric acid reducing agents are particularly preferred the agents ranitidine hydrochloride and aluminum sucrose hydrogen sulfate selected. Both agents are for the invention Suitable for pharmaceuticals and generally well tolerated.
  • Substances effective as antigen are preferably natural or synthetic antigens and / or antigen mimotopes are used.
  • the used natural or synthetic antigens or antigen mimotopes or mixtures thereof cause an after oral intake Immune response, which refers to the formation of immunoglobulins.
  • the immunoglobulins IgE and IgG1 are preferably formed.
  • a Linker coupled to a macromolecular support.
  • a macromolecular Carriers are pharmacologically acceptable substances, in particular, KLH (Keyhole Limpet Hemocyanin), TT (Tetanus toxoid) and ABP (streptococcal albumin-binding protein) mentioned. This makes the immunogenicity of the antigen effective Substances increased.
  • the medicinal products are known as antigen mimotopes Contain monomers, dimers, trimers or oligomers, which with the macromolecular carriers are conjugated.
  • antigen mimotopes Contain monomers, dimers, trimers or oligomers, which with the macromolecular carriers are conjugated.
  • is increased Generates immunogenicity.
  • the monomeric simple or dimeric, trimeric or oligomeric antigen mimotopes are bound several times to the macromolecular carrier. This will achieved an increase in immunogenicity.
  • Drugs in which the antigens are effective are particularly preferred are particularly preferred Substance triggers an antitumor effect.

Abstract

Oral vaccine (A) comprises an antigenic agent (I) and a gastric acidity reducing agent (II), for combined or separate, simultaneous or successive administration.

Description

Die vorliegende Erfindung betrifft ein Arzneimittel zur oralen Vakzinierung.The present invention relates to a pharmaceutical for oral Vaccination.

In der Medizin ist es häufig erwünscht, dass Krankheiten nicht nur symptomatisch bekämpft werden, sondern ihr Entstehen von vorne herein verhindert wird. Im Bereich der Infektionskrankheiten, neuerdings aber auch im Bereich der Krebserkrankungen wird daher der Weg der Vakzinierung eingeschlagen. Mittels dieser Methode wird der Körper dazu befähigt, mit Hilfe seines Immunsystems auf krankheitserregende Substanzen, auch Antigene genannt, zu reagieren. Dieses auch als aktive Immunisierung bekannte Verfahren funktioniert dadurch, dass dem Immunsystem ein mit einer Krankheit assoziiertes Antigen präsentiert wird, worauf das Immunsystem mit der Bildung entsprechender spezifischer Antikörper gegen besagte Antigene reagiert. Diese sogenannten Antigene bestehen häufig aus Peptiden oder Proteinen, dass heißt Aminosäuresequenzen, welche häufig parenteral, das heißt unter Umgehung des Magen-Darm-Traktes verabreicht werden. Dies geschieht meist mittels Injektion oder Infusion, was von den Patienten häufig als unangenehm empfunden wird.In medicine, it is often desirable that not only diseases are combated symptomatically, but their emergence from the outset is prevented. In the field of infectious diseases, but more recently in the area of cancer, too, the path of Vaccination hit. With this method the body becomes this able to use his immune system to cause disease React substances, also called antigens. This also as active Known immunization procedures work in that the Immune system an antigen associated with a disease is presented whereupon the immune system with the formation of corresponding specific Antibody against said antigens reacts. These so-called antigens often consist of peptides or proteins, that is Amino acid sequences, which are often parenteral, i.e. bypassed of the gastrointestinal tract. This is usually done using Injection or infusion, which is often considered uncomfortable by patients is felt.

Dem gemäß ist es Aufgabe der vorliegenden Erfindung, eine Vakzine zur Verfügung zu stellen, mit Hilfe derer es möglich ist, eine Impfung auf parenteralem Wege zu vermeiden und die Akzeptanz bei den Patienten dadurch zu steigern.Accordingly, it is an object of the present invention to provide a vaccine To provide with the help of which it is possible to have a vaccination avoid parenteral routes and patient acceptance thereby increasing.

Der Erfindung liegt die Erkenntnis zugrunde, dass eine parenterale Applikation dann umgangen werden kann, wenn im Magenbereich geeignete Bedingungen herrschen, die die Wirksamkeit des Impfstoffes nicht beeinträchtigen.The invention is based on the finding that parenteral Application can be avoided if in the stomach area suitable conditions prevail that affect the effectiveness of the vaccine do not interfere.

Gegenstand der vorliegenden Erfindung sind Arzneimittel, die eine als Antigen wirksame Substanz und eine magensäurereduzierende Substanz als Kombinationspräparat zur gemeinsamen oder getrennten, gleichzeitigen oder zeitlich versetzten oralen Anwendung zur Vakzinierung enthalten.The present invention relates to medicinal products which are used as Antigenic substance and a gastric acid reducing substance as Combination preparation for joint or separate, simultaneous or contain staggered oral application for vaccination.

Durch diese Arzneimittel wird zum einen ermöglicht, dass die als Antigen wirksame Substanz gleichzeitig mit der magensäure-reduzierenden Substanz eingenommen werden kann, wobei beide Phasen zusammen oder getrennt vorliegen. Zum anderen kann das Kombinationspräparat auch in der Weise appliziert werden, dass die als Antigen wirksame Substanz getrennt und nach der Applikation einer geeigneten Dosis an magensäurereduzierender Substanz verabreicht wird. Dabei ist es wichtig, dass die Magensäure zum Zeitpunkt der Applikation, das heißt zu dem Zeitpunkt, an dem der Impfstoff in den Magen gelangt, im Vergleich zum "normalen Magensäuregehalt" reduziert ist. Auf diese Weise wird es ermöglicht, dass eine traditionell parenteral zu verabreichende Vakzine auch oral appliziert werden kann und ihre Wirkung in Form der Erzeugung einer Immunantwort entfalten kann. Des weiteren hat die reduzierte Azidität auch eine Nicht-Aktivierung der Magen-Proteasen zur Folge, denn Pepsinogene werden erst durch den niedrigen pH im Magen zu den aktiven Pepsinen gespalten.On the one hand, these medicinal products make it possible for them to act as antigens active substance simultaneously with the gastric acid-reducing Substance can be taken, both phases together or available separately. On the other hand, the combination preparation can also be used in be applied in such a way that the substance which acts as an antigen separately and after application of a suitable dose gastric acid reducing substance is administered. It is important that the stomach acid at the time of application, that is to say When the vaccine got into the stomach compared to "normal gastric acidity" is reduced. That way it will enables a traditional parenteral vaccine can also be administered orally and its effect in the form of generation can develop an immune response. Furthermore, the reduced Acidity also results in non-activation of the gastric proteases, because Pepsinogens only become active through the low pH in the stomach Split pepsins.

Bevorzugter Weise dienen die Arzneimittel zur Vakzinierung von Säugetieren. Da auch Tiere sowohl Tumoren entwickeln können, als auch in der Lage sind, IgE zu produzieren, ist auch im veterinärmedizinischen Bereich an eine Vakzinierung gemäß der vorliegenden Erfindung zu denken. Weiterhin wird auch vermutet, dass IgE bei der Abwehr von parasitären Infektionen bei Tieren eine Rolle spielt, womit sich auch auf diesem Gebiet ein Anwendungsbereich der vorliegenden erfindungsgemäßen Vakzinierung ergibt. Besonders bevorzugt dienen die erfindungsgemäßen Arnzeimittel zur Vakzinierung von Menschen.The drugs are preferably used to vaccinate Mammals. Because animals can both develop tumors as well are able to produce IgE is also used in veterinary medicine Vaccination range according to the present invention think. Furthermore, it is also suspected that IgE in the defense against Parasitic infections in animals play a role, which also affects in this area an area of application of the present vaccination according to the invention results. The serve particularly preferably Medicines according to the invention for the vaccination of humans.

Bei einer gleichzeitigen Gabe von Arzneimitteln, die eine als Antigen wirksame Substanz und eine magensäurereduzierende Substanz umfassen, kann die als Antigen wirksame Substanz im Magen gleichzeitig oder mit zeitlicher Verzögerung im Vergleich zur magensäurereduzierenden Substanz abgegeben werden. Wichtig ist dabei nur, dass das Magenmilieu in der Weise eingestellt ist, dass die als Antigen wirksame Substanz ihre Wirkung bezüglich der Erzeugung einer Immunantwort entfalten kann. Pathophysiologisch oder iatrogen induziert können manche Individuen aus unterschiedlichen Gründen eine reduzierte Magensäure haben. Für die erfindungsgemäße Vakzinierung ist es jedoch notwendig, gezielt und kontrolliert den Säuregehalt zu beeinflussen.With simultaneous administration of drugs, one as an antigen active substance and a gastric acid reducing substance, can act as an antigen in the stomach at the same time or with time delay compared to the gastric acid reducing Substance are released. It is only important that the gastric environment is set in such a way that the substance acting as antigen is its Can have an effect on the generation of an immune response. Some individuals can be pathophysiologically or iatrogenically induced have reduced stomach acid for various reasons. For the However, vaccination according to the invention is necessary, targeted and controls to influence the acidity.

Der genaue Wirkmechanismus ist noch unbekannt, es wird jedoch vermutet, dass das Antigen unter hypoaziden Bedingungen konformationell intakt bleibt, wobei Konformationsepitope möglicherweise für die Induktion von IgE Antikörpern ausschlaggebend sind. Eine erhöhte Resorptionsrate des Antigens durch die Magenwand konnte bisher noch nicht festgestellt werden.The exact mechanism of action is still unknown, but it is suspected that the antigen is conformationally intact under hypoacid conditions remains, with conformation epitopes possibly for the induction of IgE antibodies are crucial. An increased rate of absorption of the Antigens through the stomach wall have not yet been identified become.

Bevorzugt besteht die magensäurereduzierende Substanz aus einer die Magensäurebildung inhibierenden und/oder die Magensäure bindenden Substanz. Damit wird gewährleistet, dass die Art und Weise wie es zur Magensäurereduktion kommt auf unterschiedlichen Wirkmechanismen beruhen kann. Durch solche Mittel kann die Magensäurekonzentration auf die Bedürfnisse der erfindungsgemäßen Vakzinierung eingestellt werden.The gastric acid-reducing substance preferably consists of a Inhibiting gastric acid formation and / or binding the gastric acid Substance. This ensures that the way it is used Gastric acid reduction comes from different mechanisms of action can be based. The stomach acid concentration can be increased by such means the needs of the vaccination according to the invention are adjusted.

Bevorzugt werden als magensäurereduzierende Mittel solche ausgewählt, die den Wirkstofffamilien der Antazida, H2-Rezeptor-Antagonisten oder Protonenpumpeninhibitoren angehören. Durch das Verabreichen von Antazida, d.h. basischen Mitteln, wird vorhandene Magensäure reduziert. H2-Rezeptor-Antagonisten inhibieren hingegen Histamin H2-Rezeptoren kompetitiv und reversiv, wobei die Magensäurebildung vermindert wird. Protonenpumpeninhibitoren reduzieren ihrerseits die Magensäure durch direkte Beeinflussung der Säuresekretion.Preferred gastric acid reducing agents are those which belong to the families of active substances of the antacids, H 2 receptor antagonists or proton pump inhibitors. By administering antacids, ie basic agents, existing stomach acid is reduced. H 2 receptor antagonists, on the other hand, inhibit histamine H 2 receptors competitively and reversibly, thereby reducing gastric acid formation. Proton pump inhibitors in turn reduce gastric acidity by directly influencing acid secretion.

Als Beispiele für Antazida seien folgende Wirkstoffe genannt: Natriumhydrogencarbonat, Calciumcarbonat, Magnesiumcarbonat, Magnesiumhydroxid und Magnesiumhydroxid-Gel, Magnesiumsilikat, Aluminiumphosphat, Aluminiumhydroxid und Aluminiumhydroxid-Gel, Hydrotalcite, Magaldrate, Dihydro-Aluminium-Natriumcarbonat, Magnesium-Aluminathydrat, Aminoessigsäure sowie Wismuth-Salze. Als protektiv über die Schleimhaut wirksame Substanzen seien Carbenoxolon und Sucralat (Aluminiumhydroxid und Saccharosesulfat) zu nennen. Als Beispiele für H2-Rezeptorblocker seien exemplarisch genannt: Cimetidin, Ranitidin, Oxmetidin, Famotidin, Roxatidin und Nizatidin. Als Beispiele für Protonenpumpeninhibitoren seien genannt: Omezaprol, Lansoprazol, Pantoprazol und Rabeprazol. Da Anticholinergika u.a. eine Hemmung der Speichel- u. Magensaftabsonderung bewirken, können auch Vertreter dieser Klasse verwandt werden, so z.B. Pirenzepin.The following active substances may be mentioned as examples of antacids: sodium hydrogen carbonate, calcium carbonate, magnesium carbonate, magnesium hydroxide and magnesium hydroxide gel, magnesium silicate, aluminum phosphate, aluminum hydroxide and aluminum hydroxide gel, hydrotalcites, magaldrate, dihydroaluminum sodium carbonate, magnesium aluminate hydrate, aminoacetic acid and bismuth salts , Carbenoxolone and sucralate (aluminum hydroxide and sucrose sulfate) may be mentioned as substances which have a protective action via the mucous membrane. Examples of H 2 -receptor blockers are: cimetidine, ranitidine, oxmetidine, famotidine, roxatidine and nizatidine. Examples of proton pump inhibitors are: omezaprol, lansoprazole, pantoprazole and rabeprazole. Since anticholinergics include an inhibition of saliva u. Gastric juice secretion can also be used, representatives of this class, such as Pirenzepin.

Besonders bevorzugt werden solche magensäurereduzierenden Mittel aus den Mitteln Ranitidin-Hydrochlorid und Aluminium-Saccharose-Hydrogen-Sulfat ausgewählt. Beide Mittel sind für die erfindungsgemäßen Arzneimittel geeignet und im allgemeinen gut verträglich.Such gastric acid reducing agents are particularly preferred the agents ranitidine hydrochloride and aluminum sucrose hydrogen sulfate selected. Both agents are for the invention Suitable for pharmaceuticals and generally well tolerated.

Als Antigen wirksame Substanzen werden vorzugsweise natürliche oder synthetische Antigene und/oder Antigen-Mimotope verwendet. Die verwendeten natürlichen oder synthetischen Antigene bzw. Antigen-Mimotope oder Gemische davon bewirken nach der oralen Einnahme eine Immunantwort, die sich auf die Bildung von Immunglobulinen bezieht. Bevorzugt werden die Immunglobuline IgE und IgG1 gebildet.Substances effective as antigen are preferably natural or synthetic antigens and / or antigen mimotopes are used. The used natural or synthetic antigens or antigen mimotopes or mixtures thereof cause an after oral intake Immune response, which refers to the formation of immunoglobulins. The immunoglobulins IgE and IgG1 are preferably formed.

Bei Arzneimitteln, die natürliche oder synthetische Antigene und/oder Antigen-Mimotope enthalten, werden diese bevorzugter Weise über einen Linker an eine makromolekularen Träger gekoppelt. Als makromolekulare Träger kommen pharmakologisch verträgliche Substanzen in Frage, insbesondere seien KLH (Keyhole Limpet Hemocyanin), TT (Tetanustoxoid) und ABP (streptococcal Albumin-binding Protein) erwähnt. Damit wird die Immunogenität der als Antigen wirksamen Substanzen gesteigert.In the case of medicinal products containing natural or synthetic antigens and / or Containing antigen mimotopes, these are preferred over a Linker coupled to a macromolecular support. As a macromolecular Carriers are pharmacologically acceptable substances, in particular, KLH (Keyhole Limpet Hemocyanin), TT (Tetanus toxoid) and ABP (streptococcal albumin-binding protein) mentioned. This makes the immunogenicity of the antigen effective Substances increased.

Es ist weiterhin möglich, dass die Arzneimittel Antigen-Mimotope als Monomere, Dimere, Trimere oder Oligomere enthalten, welche mit dem makromolekularen Träger konjugiert sind. Auch hier wird eine erhöhte Immunogenität erzeugt. Weiterhin ist bevorzugt, dass die monomeren, dimeren, trimeren oder oligomeren Antigen-Mimotope einfach oder mehrfach an den makromolekularen Träger gebunden sind. Dadurch wird eine Steigerung der Immunogenität erzielt.It is also possible that the medicinal products are known as antigen mimotopes Contain monomers, dimers, trimers or oligomers, which with the macromolecular carriers are conjugated. Here, too, is increased Generates immunogenicity. It is further preferred that the monomeric simple or dimeric, trimeric or oligomeric antigen mimotopes are bound several times to the macromolecular carrier. This will achieved an increase in immunogenicity.

In Bezug auf die Einsetzbarkeit der als Antigen fungierenden Substanzen in den erfindungsgemäßen Arzneimitteln sind zahlreiche Möglichkeiten denkbar. Zu nennen wären beispielsweise als Antigen wirksame Substanzen, die mit Infektionskrankheiten wie etwa bakteriellen oder viralen Infektionskrankheiten assoziiert sind. With regard to the applicability of the substances acting as antigen in The medicaments according to the invention are numerous possibilities conceivable. For example, effective antigens should be mentioned Substances associated with infectious diseases such as bacterial or viral infectious diseases are associated.

Besonders bevorzugt sind Arzneimittel, bei denen die als Antigen wirksame Substanz eine antitumorale Wirkung auslöst. Gerade im Bereich der Krebstherapie und Krebsvorsorge sind Vakzinierungen und insbesondere der Vorteil einer möglichen oralen Vakzinierung für die Patienten erwünscht.Drugs in which the antigens are effective are particularly preferred Substance triggers an antitumor effect. Especially in the area of Cancer therapy and cancer screening are vaccinations and in particular the benefit of possible oral vaccination for the patient he wishes.

Nachstehend sind Beispiele der erfindungsgemäßen oralen Vakzinierung erläutert. Zur Erklärung zeigt:

Figur 1:
Den IgE-Anstieg in den verschiedenen Mausgruppen gegen das Antigen, gemessen im ELISA (Scala: OD-Werte).
  • Gruppe A: Orale Gabe von Zantac und Antigen
  • Gruppe B: Orale Gabe von Ulcogant und Antigen
  • Gruppe C: Vergleichsbeispiel mit intraperitonealer Gabe von Antigen und Aluminiumhydroxid als Adjuvans
  • Gruppe D: Orale Gabe des Antigens
    •
    Examples of the oral vaccination according to the invention are explained below. Explanation shows:
    Figure 1:
    The IgE increase in the different mouse groups against the antigen, measured in an ELISA (Scala: OD values).
  • Group A : Oral administration of Zantac and antigen
  • Group B : Oral administration of ulcogant and antigen
  • Group C : Comparative example with intraperitoneal administration of antigen and aluminum hydroxide as adjuvant
  • Group D : Oral administration of the antigen

    • Befunde gemäß der vorliegenden Erfindung machen deutlich, dass eine Hypoazidität des Magens (durch Antazida-Behandlung z.B. wegen eines Ulcus venticuli) bei gleichzeitiger erstmaligen Einnahme eines Antigens zu einer IgE Induktion spezifisch gegen dieses neue Antigen führt. Diese Situation wurde im Tiermodell überprüft und folgende Resultate wurden erhalten (Figur 1):Findings according to the present invention make it clear that a Hypoacidity of the stomach (due to antacid treatment e.g. because of a Ulcus venticuli) with simultaneous first intake of an antigen an IgE induction specifically against this new antigen. This Situation was checked in the animal model and the following results were received (Figure 1):

    Gängige Präparate, welche die Magensäurebildung inhibieren (Zantac [Ranitidin-Hydrochlorid, GaxoSmithKline]) oder welche die Magensäure binden und neutralisieren (Ulcogant [Aluminium-Saccharose-Hydrogensulfat, Merck]), bewirken eine nachhaltige Induktion von IgE und auch IgG Antikörpern gegen ein gleichzeitig gefüttertes neues Nahrungsmittel, jedoch nicht gegen die tägliche Diät der Mäuse, gegen welche sie weiter tolerant blieben. Die erzielten IgE-Werte sind auch im Vergleich zu einer traditionellen Allergisierung auf intraperitonealem Weg mit Al(OH)3 als Adjuvans hoch. Common preparations which inhibit gastric acid formation (Zantac [ranitidine hydrochloride, GaxoSmithKline]) or which bind and neutralize gastric acid (Ulcogant [aluminum-sucrose hydrogen sulfate, Merck]) cause a sustainable induction of IgE and also IgG antibodies against one at the same time fed new food, but not against the daily diet of the mice to which they remained tolerant. The IgE values achieved are also high compared to traditional allergy by the intraperitoneal route with Al (OH) 3 as adjuvant.

    Aufgrund der vermehrten Literaturberichte, welche auf eine anti-Tumorwirkung von IgE Antikörpern hinweisen (Reali, E.; Greiner, J.W.; Corti, A.; Gould, H.J., Bottazzoli, F.; Paganelli, G.; Schlom, J.; Siccardi, A.G.; Cancer Res., 2001; 61(14): 5517-22; Kershaw, M.H., Darcy, P.K.; Trapani, J.A.; MacGregor, D.; Smyth, m.J.; Oncol. Res., 1998, 10(3), 133-42; Neuchrist, C.; Kornfehl, J.; Grasl, M.; Lassmann, H.; Kraft, D.; Ehrenberger, K.; Scheiner, O.; Int. Archs. Allergy Immunol., 1994, 104: 97-100; Nagy, E.; Berczi, I.; Sehon, A.H.; Cancer Immunol. Immunother. 1991; 34(1): 63-9), kann mit einem positiven Effekt einer Vakzinierung durch orale Applikation von Tumor-Mimotopantigenen gerechnet werden.Due to the increased number of literature reports that indicate an anti-tumor effect of IgE antibodies (Reali, E .; Greiner, J.W .; Corti, A .; Gould, H.J., Bottazzoli, F .; Paganelli, G .; Schlom, J .; Siccardi, A.G .; Cancer Res., 2001; 61 (14): 5517-22; Kershaw, M.H., Darcy, P.K .; Trapani, J.A .; MacGregor, D .; Smyth, M.J .; Oncol. Res., 1998, 10 (3), 133-42; Neuchrist, C .; Kornfehl, J .; Grasl, M .; Lassmann, H .; Kraft, D .; Ehrenberger, K .; Scheiner, O .; Int. Archs. Allergy Immunol., 1994, 104: 97-100; Nagy, E .; Berczi, I .; Sehon, A.H .; Cancer Immunol. Immunother. 1991; 34 (1): 63-9), can have a positive effect of vaccination by oral application of tumor mimotopantigens.

    Claims (9)

    Arzneimittel, enthaltend eine als Antigen wirksame Substanz und eine magensäurereduzierende Substanz als Kombinationspräparat zur gemeinsamen oder getrennten, gleichzeitigen oder zeitlich versetzten oralen Anwendung zur Vakzinierung.Medicament containing an antigenic substance and a gastric acid reducing substance as a combination preparation for common or separate, simultaneous or staggered oral application for vaccination. Arzneimittel gemäß Anspruch 1, dadurch gekennzeichnet, dass die als Antigen wirksame Substanz im Magen gleichzeitig oder mit zeitlicher Verzögerung im Vergleich zur magensäurereduzierenden Substanz freigesetzt wird.Medicament according to Claim 1, characterized in that the substance which acts as an antigen is released in the stomach at the same time or with a time delay in comparison with the substance which reduces gastric acidity. Arzneimittel gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, dass die magensäurereduzierende Substanz die Magensäurebildung inhibiert und/oder Magensäure bindet.Medicament according to claim 1 or 2, characterized in that the gastric acid- reducing substance inhibits gastric acid formation and / or binds gastric acid. Arzneimittel gemäß Anspruch 3, dadurch gekennzeichnet, dass das magensäurereduzierende Mittel aus Mitteln der Wirkstofffamilien der Antazida, H2-Rezeptor-Antagonisten und/oder Protonenpumpeninhibitoren ausgewählt werden.Medicament according to claim 3, characterized in that the gastric acid reducing agent is selected from agents of the active ingredient families of the antacids, H 2 receptor antagonists and / or proton pump inhibitors. Arzneimittel gemäß einem der Ansprüche 1 bis 4 dadurch gekennzeichnet, dass die als Antigen wirksame Substanz natürliche oder synthetische Antigene und/oder Antigen-Mimotope umfasst.Medicament according to one of Claims 1 to 4, characterized in that the substance which acts as an antigen comprises natural or synthetic antigens and / or antigen mimotopes. Arzneimittel gemäß Anspruch 5, dadurch gekennzeichnet, dass die natürlichen oder synthetischen Antigene und/oder Antigen-Mimotope über einen Linker an einen makromolekularen Träger gekoppelt sind.Medicament according to claim 5, characterized in that the natural or synthetic antigens and / or antigen mimotopes are coupled to a macromolecular carrier via a linker. Arzneimittel gemäß Anspruch 6, dadurch gekennzeichnet, dass die Antigen-Mimotope als Monomere, Dimere, Trimere oder Oligomere mit dem makromolekularen Träger konjugiert sind.Medicament according to claim 6, characterized in that the antigen mimotopes as monomers, dimers, trimers or oligomers are conjugated to the macromolecular carrier. Arzneimittel gemäß Anspruch 7, dadurch gekennzeichnet, dass die monomeren, dimeren, trimeren oder oligomeren Antigen-Mimotope einfach oder mehrfach an den makromolekularen Träger gebunden sind. Medicament according to claim 7, characterized in that the monomeric, dimeric, trimeric or oligomeric antigen mimotopes are bound one or more times to the macromolecular carrier. Arzneimittel nach einem der vorstehenden Ansprüche 1 bis 8, dadurch gekennzeichnet, dass die als Antigen wirksame Substanz eine anti-tumorale Wirkung auslöst.Medicament according to one of the preceding claims 1 to 8, characterized in that the substance active as an antigen triggers an anti-tumor effect.
    EP02000901A 2002-01-15 2002-01-15 Oral vaccination with naked tumor-antigen-mimotopes Expired - Lifetime EP1327450B1 (en)

    Priority Applications (15)

    Application Number Priority Date Filing Date Title
    ES02000901T ES2294051T3 (en) 2002-01-15 2002-01-15 ORAL VACCINATION WITH NUDE MIMOTOPES OF TUMOR ANTIGENS.
    DE50210696T DE50210696D1 (en) 2002-01-15 2002-01-15 Oral vaccination with naked tumor antigen mimotopes
    EP02000901A EP1327450B1 (en) 2002-01-15 2002-01-15 Oral vaccination with naked tumor-antigen-mimotopes
    AT02000901T ATE369875T1 (en) 2002-01-15 2002-01-15 ORAL VACCINATION WITH NAKED TUMOR ANTIGEN MIMOTOPES
    AU2003212215A AU2003212215B9 (en) 2002-01-15 2003-01-15 Oral vaccination
    DE50307169T DE50307169D1 (en) 2002-01-15 2003-01-15 ORAL VACCINATION WITH THE TUMOR ANTIGEN MIMOTOP Gln-Met-Trp-Ala-Pro-Gln-Trp-Gly-Pro-Asp
    US10/501,402 US20050226894A1 (en) 2002-01-15 2003-01-15 Oral vaccination
    IL16285703A IL162857A0 (en) 2002-01-15 2003-01-15 Oral vaccination
    ES03708059T ES2286409T3 (en) 2002-01-15 2003-01-15 ORAL VACCINATION WITH THE GIN-MET-TRP-ALA-PRO-GIN-TRP-GLY-PRO-ASP TUMOR ANTIGEN MIMOTOPE.
    CA002473416A CA2473416A1 (en) 2002-01-15 2003-01-15 Oral vaccination
    AT03708059T ATE361097T1 (en) 2002-01-15 2003-01-15 ORAL VACCINATION WITH THE TUMOR ANTIGEN MIMOTOP GLN-MET-TRP-ALA-PRO-GLN-TRP-GLY-PRO-ASP
    PCT/EP2003/000369 WO2003059380A2 (en) 2002-01-15 2003-01-15 Oral vaccination
    EP03708059A EP1465658B1 (en) 2002-01-15 2003-01-15 ORAL VACCINATION WITH THE TUMOR ANTIGEN MIMOTOPE Gln-Met-Trp-Ala-Pro-Gln-Trp-Gly-Pro-Asp
    IL162857A IL162857A (en) 2002-01-15 2004-07-05 Use of an antigentically active substance and a gastric acid reducing substance for producing a vaccine for tumoral diseases
    US12/656,491 US20100183684A1 (en) 2002-01-15 2010-02-01 Oral vaccination

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    EP02000901A EP1327450B1 (en) 2002-01-15 2002-01-15 Oral vaccination with naked tumor-antigen-mimotopes

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    EP1465658B1 (en) * 2002-01-15 2007-05-02 Bio Life Science Forschungs- und Entwicklungsges.m.b.H. ORAL VACCINATION WITH THE TUMOR ANTIGEN MIMOTOPE Gln-Met-Trp-Ala-Pro-Gln-Trp-Gly-Pro-Asp

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    WO1996033732A1 (en) * 1995-04-28 1996-10-31 Oravax, Inc. Multimeric, recombinant urease vaccine
    WO1998043479A1 (en) * 1997-04-01 1998-10-08 Merieux Oravax 76 kDa, 32 kDa, AND 50 kDa HELICOBACTER POLYPEPTIDES AND CORRESPONDING POLYNUCLEOTIDE MOLECULES
    US5840332A (en) * 1996-01-18 1998-11-24 Perio Products Ltd. Gastrointestinal drug delivery system

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    US6403098B1 (en) * 1996-09-26 2002-06-11 Merck & Co., Inc. Rotavirus vaccine formulations
    WO1999007869A1 (en) * 1997-08-05 1999-02-18 University Of Florida Live recombinant vaccine comprising inefficiently or non-replicating virus

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    WO1996033732A1 (en) * 1995-04-28 1996-10-31 Oravax, Inc. Multimeric, recombinant urease vaccine
    US5840332A (en) * 1996-01-18 1998-11-24 Perio Products Ltd. Gastrointestinal drug delivery system
    WO1998043479A1 (en) * 1997-04-01 1998-10-08 Merieux Oravax 76 kDa, 32 kDa, AND 50 kDa HELICOBACTER POLYPEPTIDES AND CORRESPONDING POLYNUCLEOTIDE MOLECULES

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    * Cited by examiner, † Cited by third party
    Publication number Priority date Publication date Assignee Title
    EP1465658B1 (en) * 2002-01-15 2007-05-02 Bio Life Science Forschungs- und Entwicklungsges.m.b.H. ORAL VACCINATION WITH THE TUMOR ANTIGEN MIMOTOPE Gln-Met-Trp-Ala-Pro-Gln-Trp-Gly-Pro-Asp

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